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. Author manuscript; available in PMC: 2025 Apr 1.
Published in final edited form as: J Acquir Immune Defic Syndr. 2024 Apr 1;95(4):377–382. doi: 10.1097/QAI.0000000000003362

Relationship between adiposity and biomarkers of aging and frailty among adults aging with HIV

Vitor HF Oliveira 1, Amanda L Willig 2, Christine Horvat Davey 3, Thomas W Buford 2,4, Prema Menezes 5, Edward Cachay 6, Heidi M Crane 1, Greer A Burkholder 2, Barbara M Gripshover 3, Julia G Fleming 7, John D Cleveland 2, Allison R Webel 1
PMCID: PMC10922782  NIHMSID: NIHMS1949537  PMID: 38100820

Abstract

Background:

This study examined the relationships among adiposity, handgrip, physical function, inflammation (i.e., senescence-associated secretory phenotype [SASP] chemokines as biomarkers of aging and frailty), and sex hormones in aging people with HIV (PWH).

Methods:

This cross-sectional exploratory study included 150 PWH aged ≥40 years (67.3% of participants were males). Our measures included: 1) body mass index (BMI) and waist circumference as measures of adiposity; 2) handgrip as a measure of muscle strength; 3) Short Physical Performance Battery as a measure of physical function; 4) interleukin-6, tumor necrosis factor alpha receptor II (TNFRII), high sensitivity C-reactive protein (hsCRP), C-X-C motif chemokine 10 (CXCL10), and C-X3-C motif chemokine ligand 1 aka fractalkine as SASP chemokines; and 5) free testosterone, estradiol, sex hormone binding globulin, and dehydroepiandrosterone (DHEA) as sex hormones. Quantile regression analyses were used to identify relationships among inflammatory markers and hormones with age, adiposity, handgrip, and physical function.

Results:

74% (n=111) of participants were classified as overweight or obese and 53.3% (n=80) presented with abdominal obesity. After controlling for age and sex, BMI was positively associated with estradiol (β=0.043, p<0.01), and waist circumference was positively associated with hsCRP (β=2.151, p<0.01). After controlling for sex, age was positively associated with CXCL10 (β=0.024, p=0.03) and TNFRII (β=2.205, p=0.01). After controlling for age and sex, SPPB was negatively associated with DHEA (β=−0.004, p=0.01); no statistically significant associations were observed for handgrip.

Conclusion:

Adiposity levels and aging were associated with inflammation (i.e., CXCL10, TNFRII, and hsCRP) among PWH aged 40 years and older.

Keywords: Frailty, HIV, Biomarkers, Inflammation, Geriatrics

INTRODUCTION

Nearly half of people living with HIV (PWH) in the U.S. are 50 years or older, and the number of aging PWH is continuing to grow.1 A significant obstacle to achieving increased healthspan is the decline in physiological function that occurs with advancing age, which culminates in disability, frailty, and ultimately death.2,3 Thus, there is a need to better understand the relationships between aging and age-related chronic diseases in the context of HIV.4 Impaired physiological function with aging is a well-established predictor of mortality in PWH and without HIV.3,5–9 For example, reduced physical function (measured with the Short Physical Performance Battery [SPPB]) has independent and interacting effects with HIV on mortality.9 PWH present with reduced muscle strength and physical function compared to people without HIV, and these impairments are observed up to 10 years earlier.10–12 These data suggest that aging in PWH occurs faster than in those without HIV, and negatively impacts the healthspan in this population.

Another challenge aging PWH face is increasing obesity. Up to two-thirds of PWH are overweight or obese.13 Increased body fat may affect skeletal muscle through multiple pathways, including hormone changes and inflammation, leading to reduced muscle strength and physical function, sarcopenia, and frailty.14 In PWH, inflammatory markers remain elevated compared with controls without HIV, even with effective antiretroviral therapy (ART), and have an important role in the course of HIV infection.15 Aging-associated sex hormone changes also increase body fat accumulation and strongly predict muscle strength and physical function loss. However, the interplay among adiposity, inflammation, and physical function is under-studied in PWH.

As single biomarkers cannot encompass the complexity of human aging, using a biomarkers panel has been proposed to understand such processes.16–19 For example, the senescence-associated secretory phenotype (SASP), a potential driver of age-related dysfunction and related to multiple age-related conditions, is typically assessed by a few dozen secreted proteins that can mediate chronic inflammation and stimulate the growth and survival of tumor cells.20 In this regard, recent reviews have tried to identify panel biomarkers of aging and aging-associated conditions.17,18 Interleukin-6 (IL-6), tumor necrosis factor-alpha receptor II (TNFRII), and high sensitivity C-reactive protein (hsCRP) are considered inflammatory biomarkers of aging suggested to be investigated in geroscience-guided clinical trials.18 Similarly, IL-6, C-X-C motif chemokine 10 (CXCL10), and C-X3-C motif chemokine ligand 1 aka fractalkine (CX3CL1) have been suggested as primary frailty inflammatory biomarkers.17 These prior studies guided the selection of biomarkers to be investigated in our sample. Thus, this study examined the relationships among adiposity, handgrip strength, physical function, inflammation (i.e., SASP chemokines as biomarkers of aging and frailty), and sex hormones in aging PWH.

METHODS

Study design

This cross-sectional exploratory study is a secondary analysis of the “Impact of Physical Activity Routines and Dietary Intake on the Longitudinal Symptom Experience of People Living with HIV” (PROSPER-HIV) study (R01NR018391),21 an ongoing multi-site, prospective, observational study of 706 PWH from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort.22 As part of the PROSPER-HIV study, participants complete an enhanced patient-reported outcomes assessment, objective measures of physical activity, diet intake, physical function, and anthropomorphic factors. The PROSPER-HIV study aims to examine the effect of physical activity and dietary intake as effective symptom management strategies. Plasma samples from the CNICS biological specimen repository were used to analyze inflammation markers and sex hormones.

Participants

This study included 150 PROSPER-HIV study participants from three different sites (Case Western Reserve University, Cleveland, OH; University of Alabama at Birmingham, Birmingham, AL; Fenway Health, Boston, MA) that had stored CNICS plasma samples at the time of their PROSPER-HIV Study initial visit. Participants were included according to the following criteria: a) active CNICS (i.e., they must have a CNICS consent and have completed the current patient-reported outcomes assessment) and PROSPER-HIV participants; b) age ≥40 years; c) prescribed ART; d) HIV Viral Load <200 copies/mL; and e) availability of blood samples collected during routine CNICS visit. Potential CNICS participants were excluded from enrollment in PROSPER-HIV if they (1) were pregnant, breastfeeding, or planning a pregnancy at the time of study enrollment; (2) did not have telephone or internet access to complete dietary recalls; or (3) planned to move out of the area in the next 36 months. The study was approved by a reliant review of the IRB at each participating institution under the University of Washington, Seattle, WA. The PROSPER-HIV study is registered at ClinicalTrials.gov #NCT03790501.

Although older adults with HIV are typically defined as those aged ≥50 years,23 we included those ≥40 years for three reasons: 1) Muscle strength and physical function among middle-aged and older PWH is usually lower than their younger counterparts;10–12 2) A younger cutoff allows more variability in age to examine in analyses; and 3) Declines in muscle strength and physical function in PWH begin in the 40’s and examining correlates from a life course perspective may be advantageous, particularly in identifying early indicators of decline and implications for interventions.

Measures

To address our study aim, we examined: 1) body mass index (BMI) and waist circumference as measures of adiposity; 2) handgrip as a measure of muscle strength; 3) SPPB as a measure of physical function; 4) IL-6, TNFRII, hsCRP, CXCL10, and CX3CL1 as SASP chemokines; and 5) free testosterone, estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA) as sex hormones.

BMI was calculated using weight and height measures collected as part of CNICS routine clinical care visits. Waist circumference was measured during the PROSPER-HIV study visit in duplicate at the top of the iliac crest using a tape measure to the nearest 0.1 cm and averaged. It is considered a valid anthropometric predictor of abdominal visceral obesity.24

Muscle strength and physical function were assessed during the PROSPER-HIV study visit using handgrip and the SPPB, respectively. The handgrip strength was measured using the Jamar hand-held dynamometer. Each participant was asked about recent hand injuries and surgery and, in the absence of those, completed three trials with the dominant hand. The maximum strength was recorded as the endpoint. The SPPB is a well-regarded, valid (test-rest reliability=0.87), objective assessment of physical function (particularly lower extremity function),25 that includes a four-meter timed walk, five times sit-to-stand, and balance testing of increasing difficulty.21,25 Both handgrip and SPPB are associated with short-term mortality, disability, hospitalizations, and nursing home admission.7,25–28

SASP chemokines included biomarkers of aging (i.e., IL-6, TNFRII, and hsCRP) and frailty (i.e., IL-6, CXCL10, and CX3CL1) suggested in recent reviews.17,18 These biomarkers were measured in participants’ plasma using the ProQuantum strategy developed by Invitrogen (Carlsbad, CA). The polymerase chain reaction was performed in-house using the Applied Biosystems 7500 RT-PCR platform and ProQuant software. Sex hormones included measures of testosterone, E2, SHBG, and DHEA using enzyme-linked immunosorbent assays (ELISAs), plate-based assays for detecting and quantifying a specific protein in a complex mixture. To standardize the laboratory analyses, samples from the three PROSPER-HIV study sites were shipped frozen to the University of Washington, Seattle, WA, and analyses were conducted at the School of Nursing Biobehavioral Laboratory.

Statistical analysis

Descriptive statistics are presented as median (interquartile interval) for continuous variables and prevalence (percentage) for categorical variables. The Kolmogorov–Smirnov test was used to verify the normality of data, which demonstrated that it was non-normally distributed. Spearman correlation was used to identify potential relationships among the variables. To identify relationships among inflammatory markers and hormones with age, adiposity, handgrip, and physical function, quantile regression analyses were performed using the median. Regression models involving age were controlled by sex, and regression models involving adiposity, handgrip, and physical function were controlled by age and sex. Values of hormones and inflammatory markers that were ±3 standard deviations were considered outliers, and were removed after we performed separate analyses with and without outliers to assess the impact on results and observed no differences. All analyses were performed using SPSS 27.0 (SPSS Inc., Chicago, IL, USA), and a p≤0.05 was considered significant.

RESULTS

Our sample had a median of 56.0 (interquartile range 50.0–63.0) years and was composed of 67.3% (n=101) men. Participants had well-controlled HIV and had been in clinical care for HIV for 10.0 (6.0-17-0) years. Complete sample characteristics are presented in Table 1.

Table 1.

Sample characteristics.

Variables Total n=150
Demographic
Age (years) 56.0 (50.0–63.0)
Aged 50 years or more (%) 116 (77.3)
Male participants (%) 101 (67.3)
Race
 Black/African American (%) 94 (63.3)
 White (%) 54 (36.1)
 Other (%) 2 (0.7)
Employed full or part-time (%) 65 (43.3)
Hazardous drinking (AUDIT-C, %) 14 (9.3)
CD4+ T-cell count (cells/μl) 693.0 (473.0–972.0)
Time in HIV care (years) 10.0 (6.0–17.0)
Antiretroviral Therapy
 NRTIs (%) 60 (40.0)
 NNRTIs (%) 11 (7.3)
 Protease Inhibitor (%) 28 (18.7)
 Integrase Inhibitor (%) 116 (77.3)
Adiposity, handgrip and physical function
Body mass index (kg/m2) 27.9 (24.6–32.8)
Body mass index categories
 Underweight (%) 4 (2.7)
 Normal weight (%) 35 (23.3)
 Overweight (%) 57 (38.0)
 Obese (%) 54 (36.0)
Waist circumference (cm) 100.8 (92.0–113.0)
High waist circumference (%) 80 (53.3)
Grip strength (kg) 32.0 (22.1–43.5)
Low grip strength (%) 20 (13.3)
SPPB score 11.0 (9.0–12.0)
Low SPPB score (%) 25 (16.7)
Inflammatory markers and hormones
CXCL1 (pg/ml) 1227.6 (653.0–1600.9)
CXCL10 (pg/mL) 154.9 (109.1–222.7)
IL-6 (pg/ml) 7.0 (3.4–12.7)
hsCRP (mg/L) 2.8 (1.5–5.0)
Testosterone (ng/dL) 127.7 (82.5–173.4)
SHBG (nmol/L) 60.4 (34.5–85.9)
TNFRII (pg/ml) 6.4 (5.3–7.1)
Estradiol (pg/mL) 50.1 (32.6–66.1)
DHEA (ug/dL) 52.4 (23.8–125.3)
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Notes: Continuous variables are presented as median (interquartile interval) and categorical variables are presented as absolute values (percentage). AUDIT-C=The Alcohol Use Disorders Identification Test-Concise. NRTIs=Nucleoside reverse transcriptase inhibitors. NNRTIs=Non-nucleoside reverse transcriptase inhibitors. SPPB=Short Physical Performance Battery. CXCL1=C-X-C motif chemokine ligand 1. CXCL10=C-X-C motif chemokine ligand 10. IL-6=Interleukin-6. hsCRP= high sensitivity C-Reactive Protein. SHBG=Sex Hormone Binding Globulin. TNFRII=Tumor Necrosis Factor alpha Receptor II. DHEA=Dehydroepiandrosterone. Hazardous drinking (AUDIT-C) was determined when scores were ≥4 for men and ≥3 for women. Waist circumference was classified according to the World Health Organization, in which a measure >102 cm for men and >88 cm for women were considered a high waist circumference. Handgrip strength and SPPB were classified according to the European Working Group on Sarcopenia in Older People, in which measures of handgrip <27 kg for men and <16 kg for women were considered as low strength, and SPPB scores ≤8 points were considered as low SPPB. Antiretroviral therapy regimens do not equal 100% as participants are prescribed multiple classes simultaneously.

Adiposity measures showed that 74.0% (n=111) of participants were classified as overweight or obese according to their BMI, and 53.3% (n=80) presented with abdominal obesity, as determined by high waist circumference values. BMI was initially correlated (p≤0.05) with hsCRP (r=0.232), testosterone (r=−0.215), and estradiol (r=0.172). Waist circumference was initially correlated with hsCRP (r=0.331) and SHBG (r=−0.173). After controlling for age and sex (Table 2), we observed that BMI remained positively associated with estradiol (β=0.043, p<0.01), and waist circumference remained positively associated with hsCRP (β=2.151, p<0.01).

Table 2.

Quantile regression analyses results for the statistically significant associations between inflammatory markers and hormones with age, adiposity, handgrip, and physical function.

Parameters Coefficient 95% Confidence Interval (Lower bound;upper bound) p
BMI × Estradiol 0.043 0.014;0.071 <0.01
Waist × hsCRP 2.151 1.029;3.272 <0.01
Age × CXCL10 0.024 0.002;0.047 0.03
Age × TNFRII 2.205 0.501;3.909 0.01
SPPB × DHEA −0.004 −0.007;−0.001 0.01
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Notes: BMI=Body Mass Index. hsCRP= high sensitivity C-Reactive Protein. CXCL10=C-X-C motif chemokine ligand 10. TNFRII=Tumor Necrosis Factor alpha Receptor II. SPPB=Short Physical Performance Battery. DHEA=Dehydroepiandrosterone. Regression models involving age were controlled by sex, and regression models involving adiposity, handgrip, and physical function were controlled by age and sex.

Aiming to identify aging and frailty biomarkers, we analyzed differences in inflammatory markers and hormones by age, handgrip strength, and physical function levels (Supplemental Table 1). Age was initially correlated with CXCL10 (r=0.170, p=0.04) and TNFRII (r=0.211, p<0.01). Handgrip was correlated with testosterone (r=0.317, p<0.01) and SPPB was inversely correlated with DHEA (r=−0.161, p=0.05). After controlling for sex (Table 2), age remained positively associated with both CXCL10 (β=0.024, p=0.03) and TNFRII (β=2.205, p=0.01). After controlling for age and sex (Table 2), SPPB remained negatively associated with DHEA (β=−0.004, p=0.01); no statistically significant associations were observed for handgrip.

DISCUSSION

In this exploratory study aiming to identify biomarkers of aging and disability among PWH, increased adiposity was associated with higher levels of hsCRP (waist circumference) and estradiol (BMI). Furthermore, older age was associated with higher levels of CXCL10 and TNFRII, and increased SPPB scores were associated with lower DHEA.

In agreement with studies that demonstrated an increasing prevalence of obesity among PWH,13 we observed increased adiposity measured by standard BMI criteria (i.e., BMI≥25 kg/m2) and waist circumference, which are associated with numerous metabolic and inflammatory effects among PWH, having implications for morbidity and mortality.29–32 The relationship between abdominal adiposity and adipokines may be exacerbated in PWH because ART toxicity can alter the hemostatic regulation of adipokines.33 In our study, increased abdominal adiposity was associated with higher levels of hsCRP, which appears central in both adiposity- and sarcopenia-associated inflammation.15 Even though hsCRP was not augmented in participants with low handgrip or low SPPB among our participants, Erlandson et al.34 have previously demonstrated that frailty was associated with 69% higher hsCRP concentrations (p<0.01) among men with HIV (n=296), independent of comorbid conditions.

Another factor associated with inflammatory changes in our sample was age; increased age was associated with higher levels of CXCL10 and TNFRII. CXCL10 is considered one of the most useful biomarkers for a range of infectious and inflammatory conditions but is also shown to increase in humans with age. CXCL10 is considered a primary inflammatory biomarker of frailty,17 and its pathways include a decrease in mitochondrial activity, the induction of apoptosis, and a decrease in cell proliferation. CXCL10 has been investigated among PWH, and higher levels of CXCL10 were associated with disease progression (i.e., higher HIV viral load and lower T-CD4 cells),35,36 increased HIV-associated neurocognitive disorder,37 among other factors. TNFRII is also an important inflammatory biomarker that is suggested as an aging biomarker;18 among people without HIV, TNF alpha is associated with mortality risk.38,39 Although differences in these biomarkers were not observed when comparing handgrip and SPPB levels, systemic inflammatory events often precede and are hypothesized to contribute to disability and frailty in the long term.

HIV infection and adiposity are associated with hormonal changes,40,41 and aging-associated sex hormonal changes may trigger muscle loss, decreased functional performance, and decreased lifespan.42 For example, the transition to menopause is characterized by intense changes in body composition and hormones, and among women living with HIV, a study has shown that those with low physical function had experienced a longer time since menopause (12.66±2.0 versus 5.39±1.96 years, p<0.01) than women with high physical function.43 In our sample, higher BMI was associated with higher levels of estradiol, a relationship also observed in people without HIV.44,45 High estradiol levels can be deleterious for health, leading to hormonal imbalance and endocrine disruption, and therefore affecting other outcomes such as physical function.44,45 Another relationship observed was that higher SPPB was associated with lower levels of DHEA, which is a precursor to other sex hormones like testosterone and estrogen. Some research suggests a potential link between DHEA levels and physical function, particularly in the context of aging. DHEA levels tend to decline with age, and lower levels of DHEA correlate with poorer performance on tests of physical functioning by middle age in people without HIV.46 In PWH, frailty was associated with lower testosterone (17% lower; p=0.02) and lower DHEA-S (18% lower; p=.004) among men with HIV (n=296).34 Thus, our results are contrary to what has been observed in some studies, although the overall literature on hormonal changes can present many inconclusive pieces of information. Nonetheless, the relationship between HIV, hormones, and disability is not well explored, particularly in association with adiposity, and many questions remain. Due to the variability observed in these hormones and the number of confounding factors that need to be considered, studies on the associations between sex hormones and our outcomes are challenging, and further investigations should be conducted in well-designed studies involving PWH.

Our results are limited by the lack of a healthy control group that could provide reference values for the biomarkers investigated. Additionally, BMI is limited as a measure of obesity and overall body fat, and does not necessarily reflect the body composition changes that occur with age;47 future studies could enhance these analyses using other body composition assessment methods, such as bioelectrical impedance or dual-energy X-ray absorptiometry scan. Finally, our small sample size and the cross-sectional design did not allow us to infer temporal relationships or causation. The small sample size might also have prevented us from establishing some associations that were marginally statistically significant (i.e., the association between BMI and IL-6 [β =0.148, p=0.072] and between waist circumference and SHBG [β=−0.058, p=0.061]). Specifically for waist circumference and SHBG, research shows that lower levels of SHBG are observed with increased abdominal visceral fat, insulin resistance, and type 2 diabetes among people without HIV.48,49 Considering that SHBG plays a role in regulating the bioavailability of sex hormones, the relationship between waist circumference and SHBG could be further investigated in PWH. Despite these limitations, this study enrolled a diverse sample of PWH from three different sites and investigated biomarkers that have been recently suggested in gerontology studies, which we believe are the strengths of the study.

In conclusion, adiposity levels and aging were associated with inflammation among PWH aged 40 years and over. Furthermore, associations between BMI and SPPB with sex hormones were observed. CXCL10, TNFRII, and hsCRP have been recommended as biomarkers of aging and frailty and have the potential to be further investigated in longitudinal studies of disability and frailty risk among PWH.

Supplementary Material

Supplemental Digital Content

Sources of Support:

Funding for this study was provided by the National Institute of Nursing Research under grant # R01NR018391, by an HIV/Aging Pilot Award under National Institutes on Aging grant # R33AG067069-01, and by the National Institute of Allergy and Infectious Disease CNICS Research Network under grant # R24-AI067039 at the National Institutes of Health.

Footnotes

Declaration of interests: Nothing to declare.

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